ST2 is a member of the IL-1 receptor family having 38% amino acid homology to the IL-1R. Due to differential splicing, the ST2 gene encodes at least four isoforms of protein, a soluble form (sST2), a membrane bound form (ST2L) and 2 variant ST2s (Oshikawa et al, 2001, Am J Respir Drit Care Med 164: 277). ST2 gene expression is widespread but the membrane bound form is most highly expressed on mast cells and Th2 cells. IL-33 was recently identified as the ligand for ST2. IL-33 binds a heterodimeric receptor complex consisting of ST2 and the ubiquitously expresses IL-1R accessory receptor protein (IL-1R-AP) and activates several signaling proteins including, NFκB and MAP kinases such as p38 and JNK. The IL-33/ST2 axis is involved in the promotion and maintenance of allergic inflammation via a number of cell types that include Th2 cells, mast cells and basophil, and structural cells such as airway epithelium and smooth muscle cells.
IL-33 mRNA is expressed by multiple organs and cell types in human and mice. At the protein level, IL-33 is mainly expressed by fibroblasts, epithelial cells and endothelial cells, particularly in high endothelial venules. However, in the absence of pro-inflammatory stimuli, IL-33 localizes to the nucleus. IL-33 is specifically released during necrotic cell death, which is thought to be associated with tissue damage during trauma or infection. Under these conditions, extracellular IL-33 may engage the ST2 receptor on mast cells and other immune cells in order to alert the immune system of tissue damage and infection and to promote the initiation of the healing responses. Because IL-33 is released by necrotic, but not apoptotic, cells and can recruit and activate immune cells, it has been suggested that IL-33 is an ‘alarmin’ or an endogenous danger signal as HMGB1 and IL-1α and therefore, IL-33 is proposed to have an important role in sensing damage in various infectious and inflammatory disease.
IL33/ST2 signalling is believed to function as a paracrine system to protect the heart from the maladaptive remodeling induced by mechanical stressors such as myocardial infarction (MI) and hypertension. The transcript for ST2 is markedly upregulated in mechanically-stimulated cardiomyocytes in vitro, and the cardiac ST2 transcript and serum ST2 protein are increased following the induction of myocardial infarction in vivo. A physiological function of sST2 is suggested by the protective effect of IL33 administration in cardiac overload, mediated by reducing cardiomyocyte hypertrophy and leading to reduced cardiac dysfunction and improved survival.
In contrast, sST2 inhibits the action of IL-33 by acting as a decoy receptor, and serum concentration of sST2 has been shown to be correlated to structural and functional cardiac changes consistent with the remodelling in patients with heart failure. A study analysed serum levels of sST2 in patients with non-ischaemic congestive heart failure (CHF) defined as a reduced left ventricular ejection fraction. An increase in serum ST2 levels was found to independently predict the risk for reaching a subsequent endpoint of mortality or cardiac transplantation in a multivariate model that included measurements of BNP (brain natriuretic peptide). In In mice with germline deletion of ApoE (a key factor in cholesterol metabolism, deficiency of which leads to spontaneous hypercholesterolemia and atherosclerotic disease), IL-33 reduced aortic atherosclerotic plaque development and induced serum levels of antibodies to oxidized low density lipoprotein (oxLDL), which are atheroprotective. Conversely, administration of the decoy receptor, sST2 resulted in a significantly higher aortic plaque burden compared with control mice. Thus, in both heart failure and atherosclerosis, IL-33 signalling appears beneficial, and sST2 might act as a decoy receptor to reduce IL-33 signalling through the ST2L receptor.
Advances in management of HIV disease and antiretroviral therapy (ART) during the last decade have led to prolonged disease free survival in a majority of subjects with HIV infection. Cardiovascular disease (CVD) is now a leading cause of death among HIV-infected patients. There is evidence that the rate of acute myocardial infarction (MI) in HIV-infected patients may be higher than in the general population even after adjustment for anthropometric factors, race, hypertension, diabetes and dyslipidemia. Because ST2/IL-33 signalling is involved in cardiovascular disease and inflammatory disease, the inventors examined whether sST2 levels are increased in HIV-infected patients in a first cross sectional study. Subsequently, they aimed to quantify the risk of CVD events associated with serum sST2 at baseline in the Strategies for Management of Antiretroviral Therapy (SMART) study. Their work was presented at the 6th IAS conference on HIV pathogenesis, treatment and prevention, 17 Jul. 2011